7-hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives as aldose reductase inhibitors: a SAR study

On the basis of the results of molecular modelling studies performed on the aldose reductase (ALR2) inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benz opyran-4-one (compound A) bound at the active site of the enzyme, we synthe sised and tested on bovine and human ALR2 several derivatives modified at p osition 2 of the benzopyran moiety, in order to confirm the hypothesised bi nding mode of this compound. The substitution of the methylene bridge with the isosteric sulphur substituent gives an active derivative, while substit ution with a polar NH causes a decrease in inhibitory activity; this is in accordance to the previously reported structure in which the methylene link er was found to be adjacent to a hydrophobic aminoacid (Leu300). Among the substituents at 4' position examined, the most favourable for inhibitory ac tivity are those able to act as hydrogen bond donors, supporting the hypoth esis of the importance of the interaction with Thr113 for the inhibition of the enzyme. (C) 2001 Editions scientifiques et medicales Elsevier SAS.